Abstract: Despite recent advances in immunosuppressive therapies and patient management to improve graft and patient survival following heart transplantation, cardiac allograft vasculopathy (CAV) remains a major burden on long-term patient morbidity and mortality. In fact, up to 50% of heart transplant recipients may experience CAV within five years of transplantation (1). Furthermore, recent data from the International Society for Heart and Lung Transplantation suggest that CAV and late graft failure resulting from CAV together account for 30% of deaths (2). CAV is an accelerated form of coronary artery disease (CAD) which is characterized by diffuse and progressive thickening of the intima of the entire length of the affected epicardial and intramyocardial arteries (3), and can be observed as early as six months posttransplant. The pathology of CAV is considered distinct from that of CAD, in which focal and eccentric plaques form largely in the proximal coronary vessels (4, 5). CAV appears to be initiated by endothelial cell injury which triggers both immune-mediated and non-immune-mediated changes (6). Among the immunological factors involved in the pathology of CAV are histocompatibility mismatch, chronic inflammation and episodes of acute rejection (Fig. 1) (3, 4). Non-immune-mediated factors cover a broad spectrum of transplantation-related events including cytomegalovirus infection, ischemia-reperfusion injury and cause of donor brain death. However, traditional risk factors for cardiac events such as dyslipidemia, hypertension, obesity, diabetes mellitus and smoking are also very much involved in the development of CAV (Fig. 1) (3, 4).FIGURE 1.: Proposed risk factors for the pathology of cardiac allograft vasculopathy (1, 4). CAV, cardiac allograft vasculopathy; CNI, calcineurin inhibitor; CMV, cytomegalovirus.CAV may be proximal or distal in nature, or both. While proximal disease may be amenable, if relatively localized, to stenting or bypass grafting, undetected or untreated proximal disease of moderate severity (e.g. 40% stenosis in one or more arteries) is associated with a very poor prognosis (<20% patient survival at 5 years) (7). Distal diffuse disease is associated with stuttering episodes of myocardial ischemia and diastolic dysfunction, intermittent atrial arrhythmias, cardiovascular accidents and a similarly poor outcome. CAV cannot currently be cured once established. Percutaneous transluminal coronary angioplasty with stents is often initially successful in proximal disease, but with rapid new lesion development being common. In many patients, particularly those with distal disease, re-transplantation is the only clinical option. At this stage of development of CAV, heart failure and other co-morbidities often prevent the patient being a candidate for re-transplantation. Therefore, preventing CAV in de novo heart transplant recipients and slowing the progression of CAV in patients with established disease remain key challenges for heart transplant clinicians. Reducing the level of endothelial injury is one key approach to minimizing the risk of CAV pre-transplantation. Reducing the cold ischemic time or potentially maintaining warm perfusion (8), and improving myocardial preservation during storage and transport (9) both aid post-transplant cardiac function and longevity. In the post-transplant period, approaches may include initiating an immunosuppressive regimen with antiproliferative effects and minimizing the incidence of acute rejection episodes (4). The antiproliferative effects of the proliferation signal inhibitors (PSIs), everolimus (Certican, Novartis Pharma AG, Basel, Switzerland) and sirolimus (Rapamune, Wyeth Pharmaceuticals, New Jersey, USA) are associated with a reduction in intimal thickening, and a reduced incidence of CAV both in ex vivo models (10) and in de novo heart transplant recipients (11, 12). Conversion to sirolimus in maintenance heart transplant recipients with existing CAV has previously resulted in slowing the progression of CAV and in fewer clinical events related to CAV (13). The antiproliferative effects of both of these agents have also been demonstrated in drug-eluting stents used in the treatment of CAD, showing lower rates of restenosis compared to standard bare metal stents (14, 15). Use of PSIs, however, is not completely straight forward and is associated with a now well-known side effect profile. Concerns remain about optimal usage and dosing particularly when co-administered with full-dose calcineurin inhibitors (CNI), where a complex interaction can exacerbate CNI nephrotoxicity (5, 16, 17). This may occur even in the presence of close therapeutic drug monitoring, perhaps due to pharmacogenic differences between individuals which are not yet understood. Increasing clinical experience with PSIs in combination with low-dose CNIs suggests that lower blood levels can be targeted preserving both efficacy and minimizing side effects (18). Due to cardiac denervation during transplantation, CAV often progresses silently in heart transplant recipients and typically presents late, as major adverse cardiac events (MACE) such as acute myocardial infarction or sudden death (5). In fact, diagnosis of CAV by intravascular ultrasound examination at one year post-transplant is predictive of the occurrence of MACE at five years post-transplant (19–21). Therefore, the clinical outcomes of CAV pose a large burden on healthcare resources following transplantation. The articles which comprise this supplement form a comprehensive review of the impact of CAV on healthcare burden following heart transplantation. Firstly, Dr. Maria Frigerio provides a review of the current literature on the burden of CAV in heart transplantation, assessing the limitations of different techniques used in the screening of CAV and different strategies for the treatment of CAV in both de novo and maintenance heart transplant recipients. Dr. Howard Eisen then discusses the role of the PSIs, everolimus and sirolimus, in reducing the healthcare burden of CAV in de novo and maintenance patients using data on MACE reported in clinical trials. The supplement concludes with a case study by Dr. Frigerio in which the long-term follow-up of a maintenance heart transplant recipient converted to everolimus following an acute myocardial infarction will be discussed. These articles strongly suggest that PSIs could be used in both de novo and maintenance heart transplant recipients to reduce the impact of CAV on the long-term outcomes of heart transplantation. Whether these immunosuppressive agents can cause regression of CAV has yet to be elucidated and is currently being investigated.